We wish to understand the response of mammalian cells to treatment with mutagenic chemicals. What is the mechanism of the mutation process in mammalian cells, how does the genome react with chemical agents, what is the response of the cell to the reaction products, what genetic systems control the response of the cell to mutagens, what governs the expression of mutations? In particular we wish to account for the biological activity of the alkylating agents. We wish to know how small electrophilic molecules interact with the DNA of mammalian cells in vivo to produce the spectrum of biological change recognized as mutation and chromosome aberration, and to discover the relationship between mutation and the other biological effects of alkylating agents. Since the discovery that carcinogens may be converted into electrophilic molecules in vivo, it has become clear that most carcinogens are mutagens. We would like to understand the relationship between the carcinogenic and mutagenic activities of the alkylating agents. In order to help answer these questions we propose the following: 1. Characterization of the changes produced in the DNA of human cells in culture by treatment with alkylating agents and other mutagens and determination of the mechanisms of DNA replication and repair in damaged cells. 2. Studies on the mutability of human lymphoblastoid cell lines treated with alkylating agents in an effort to determine: a) whether there are peculiarities in the process of mutation in mammalian tissue culture cells, and b) whether there is a role of repair and recombination in the establishment of mutation in mammalian cells similar to that obseved in bacteria.